1. Field of the Invention
The present invention relates to substituted 5-arylsulfonyl indoles and indolines which interact with serotonin receptors, such as 5-HT6 receptors, and are useful for treating anxiety, depression, schizophrenia, stress-related disorders such as irritable bowel syndromes panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other central nervous system (CNS) disorders in humans and animals.
The major classes of serotonin receptors (5-HT1-7) contain fourteen to eighteen separate receptors that have been formally classified. See Glennon, et al., Neuroscience and Behavioral Reviews, 1990, 14, 35; and D. Hoyer, et al. Pharmacol. Rev. 1994, 46, 157-203. There is currently a need for pharmaceutical agents that are useful to treat diseases and conditions that are associated with 5-HT receptors. In particular, there is a need for agents that can selectively bind to individual receptor sub-types (e.g. receptor-specific agonists or antagonists); such agents would be useful as pharmaceutical agents, or would be useful to facilitate the study of the 5-HT receptor family, or to aid in the identification of other compounds that selectively bind to the specific 5-HT receptors.
For example, the 5-HT6 receptor was identified in 1993 (Monsma et al. Mol. Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys. Res. Com. 1993, 193, 269-276). Several antidepressants and atypical antipsychotics bind to the 5-HT6 receptor with high affinity and this binding may be a factor in their profile of activities (Roth et al. J. Pharm. Exp. Therapeut. 1994, 268, 1403-1410; Sleight et al. Exp. Opin. Ther. Patents 1998, 8, 1217-1224; Bourson et al. Brit. J. Pharm. 1998, 125, 1562-1566; Boess et al. Mol. Pharmacol. 1998, 54, 577-583; Sleight et al. Brit. J. Pharmacol. 1998, 124, 556-562). In addition, the 5-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al. Life Sciences 1998, 17/18, 1473-1477). Together these studies and observations suggest that compounds that antagonize the 5-HT6 receptor will be useful in treating disorders of the central nervous system, such as anxiety, depression, schizophrenia, stress-related disorders such as irritable bowel syndrome, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, and epilepsy. In general, compounds of formula I exhibit selective inhibition of 5-HT6 serotonin receptors relative to the inhibition of other 5-HT serotonin receptors.
General anxiety disorder (GAD) occurs when a person worries about things such as family, health, or work when there is no reason to worry and is unable not to worry. About 3 to 4% of the U.S. population has GAD during the course of a year. GAD most often strikes people in childhood or adolescence, but can begin in adulthood, too. It affects women more often than men. Currently, treatment involves cognitive-behavioral therapy, relaxation techniques, and biofeedback to control muscle tension and medications such as benzodiazepines, imipramine, and buspirone. These drugs are effective but all have side-effect liabilities. Therefore, there is a need of a pharmaceutical agent to address the symptoms with fewer side effects.
Depression is a mood disorder of varying lengths of normally several months to more than two years and of varying degrees of feelings involving sadness, despair, and discouragement. The heterocyclic antidepressants (HCA""s) are currently the largest class of antidepressants, but monoamine oxidase inhibitors (MAOI""s) are used in particular types of depression. Common side effects from HCA""s are sedation and weight gain. In elderly patients with organic brain disease, the side effects from HCA""s can also include seizures and behavioral symptoms. The main side effects from using MAOI""s occur from dietary and drug interactions. Therefore, agents with fewer side effects would be useful.
Schizophrenia is a disease having multiple aspects. Currently available drugs are generally aimed at controlling the positive aspects of schizophrenia, such as delusions. One drug, Clozapine, is aimed at a broader spectrum of symptoms associated with schizophrenia. This drug has many side effects and is thus not suitable for many patients. Thus, there is a need for a drug to treat the cognitive and attention deficits associated with schizophrenia. Similarly, there is a need for a drug to treat the cognitive and attention deficits associated with schizoaffective disorders, or similar symptoms found in the relatives of schizophrenic patients.
Post-traumatic stress disorder (PTSD) is a form of anxiety triggered by memories of a traumatic event that directly affected the patient or that the patient may have witnessed. The disorder commonly affects survivors of traumatic events including sexual assault, physical assault, war, torture, natural disasters, an automobile accident, an airplane crash, a hostage situation, or a death camp. The affliction also can affect rescue workers at an airplane crash or a mass shooting, someone who witnessed a tragic accident or someone who has unexpectedly lost a loved one. Treatment for PTSD includes cognitive-behavioral therapy, group psychotherapy, and medications such as Clonazepam, Lorazepam and selective serotonin-reuptake inhibitors such as Fluoxetine, Sertraline, Paroxetine, Citalopram and Fluvoxamine. These medications help control anxiety as well as depression. Various forms of exposure therapy (such as systemic desensitization and imaginal flooding) have all been used with PTSD patients. Exposure treatment for PTSD involves repeated reliving of the trauma, under controlled conditions, with the aim of facilitating the processing of the trauma. Therefore, there is a need for better pharmaceutical agents to treat post-traumatic stress disorder.
Stress may increase the release of epinephrine from the adrenal medulla and norepinephrine from adrenergic neurons activated by central nervous system (CNS) stimulation. High levels of circulating epinephrine mediate alpha-adrenergic effects including increases in heart rate and cardiac output. Epinephrine may also be taken up by beta2 receptors on the presynaptic neuronal membrane and may enhance release of norepinephrine from storage granules. Transient epinephrine surges resulting from stress may produce considerably more prolonged vasoconstriction. Stress-induced activation of the sympathetic nervous system may lead to hypertension. Stress also can cause stress gastritis and affect the efficacy of medical treatment in some ulcer patients. There is a need for pharmaceutical agents to treat stress-related diseases.
Panic disorders, phobias, and obsessive compulsive behavior are forms of neurosis. They are all related to excessive anxiety. All humans experience fear and anxiety in response to an external threat, or a difficult situation. However, the neuroses noted above, are abnormal responses to ordinary situations. The causes of such neurotic disorders are not fully known.
Anxiety can arise suddenly, as in panic, or gradually over many minutes, hours, or even days. Anxiety may last for variable periods of time ranging from less than a minute to years. Brief panic attacks are common. However, most persons recover without treatment, and panic disorder is much less common.
Phobias are similar to panic attacks in that they involve anxiety. However, in the various phobias the anxiety is not the free-floating anxiety of panic disorder, but instead focuses on specific situations or stimuli. Persons who have a phobia often realize that their anxiety is excessive, but nonetheless, they tend to avoid the situations or stimuli that disturb them. If they must be exposed to such situations or stimuli they endure them with great distress. Some relatively commonly observed phobias include agoraphobia, that is, the fear of being trapped in closed places, fear of snakes, fear of heights, fear of the dark, fear of strangers, fear of storms, fear of water, heights, and fear of flying.
Persons suffering from an obsessive-compulsive disorder feel compelled to perform repetitive, purposeful, rituals to control their obsessions. For example, a person with an obsessive fear of contamination might compensate with excessive hand washing.
These panic and anxiety disorders may be treated with behavior therapy and antidepressants and benzodiazepines. Obsessive compulsive disorders may be treated with behavior therapy and various drugs such as serotonin reuptake inhibitors (SRIs), selective serotonin reuptake inhibitors (SSRIsxe2x80x94e.g., fluoxetine, fluvoxamine, paroxetine, sertraline), and clomipramine (a tricyclic antidepressant). Augmentation with haloperidol, or atypical antipsychotics may be effective. However, these drugs, especially the benzodiazepines and the antipsychotics, have potentially serious side effects. Therefore, there is a need for a pharmaceutical agent to treat these conditions.
Epilepsy is a recurrent, paroxysmal disorder of cerebral function characterized by sudden, brief attacks of altered consciousness, motor activity, sensory phenomena, or inappropriate behavior caused by excessive discharge of cerebral neurons. Treatment aims primarily to control seizures. A causative disorder may need to be treated as well. No single drug controls all types of seizures, and different drugs are required for different patients. Patients rarely require several drugs. Commonly used drugs include phenytoin, carbamazepine, or valproate gabapentin, lamotrigine, and topiramate. Therefore, there is a need for a pharmaceutical agent to treat epilepsy.
Traditionally, obesity has been defined as a body weight of  greater than 30% above ideal or desirable weight on standard height-weight tables. Currently, obesity is usually defined in terms of the body mass index (BMI)xe2x80x94weight (in kilograms) divided by the square of the height (in meters). The general cause of obesity is simplexe2x80x94expending less energy than is consumed. However, how people regulate body weight, primarily body fat, is still elusive and not fully understood. Typically, the determinants of obesity are divided into three categories: genetic, environmental, and regulatory. Recent genetic discoveries have helped explain how genes may determine obesity and how they may influence the regulation of body weight. Scientific studies estimate that genetics may account for about 33% of the variation in body weight. The remaining variation may be caused by environmental and regulatory factors. Environmental factors include socioeconomic status, large food intake, and sedentary lifestyle. Regulatory factors include pregnancy, endocrine, and psychological influences. Despite the analysis of obesity in terms of these three factors, the final common pathway to caloric balance lies in behavior mediated by the CNS. Recent attempts at pharmacotherapy of obesity has lead to widespread valvular heart disease in patients who received fenfluramine alone or in combination with phentermine (often referred to as fen-phen). Therefore, there is a need for a pharmaceutical agent to treat obesity.
General CNS diseases to be treated by the compounds of the present invention include cognitive disorders such as mild cognitive impairment, Alzhiemer""s disease, and attention deficit disorder with or without hyperactivity. Alzheimer""s disease (AD) is a complex disease related with age that slowly progresses to loss of memory and language skills, with the related problems of having difficulties in learning and making decisions and judgments. Approximately 4 million Americans are reported to be suffering from AD. Currently available drugs, tacrine, donepezil and rivostigmine, are used to only retard the progression of the disease. The above-mentioned drugs are to enhance the cholinergic transmission. However, these drugs have serious side effects. There is a need for a drug to treat AD more effectively and have fewer side effects. Meneses, A., Drug News Perspect., 2001, 14, 396-400.
2. Description of the Related Art
U.S. Pat. No. 5,637,593 and its foreign counterpart WO 94/14770 discloses tryptamine analogues that act as 5-HT1-like agonists. The compounds are expected to have utility in the treatment and/or prophylaxis of migraine, and other conditions associated with cephalic pain, such as cluster headache, headache associated with vascular disorders, and other neuralgia. They are also expected to have utility in the treatment or prophylaxis of portal hypertension.
WO 01/05793 discloses 9-arylsulfone-1,2,3,4,5,6-hexahydroazepino[4,5-]indoles which are useful in treating anxiety, depression, schizophrenia, stress related disease, panic, a phobia, obsessive compulsive disorder, obesity, and post-traumatic stress syndrome, in humans and animals.
WO 99/43654 discloses substituted indoles, and substituted idolines that act as are useful as inhibitors of phospholipase enzymes and are useful in treating or preventing inflammatory conditions in mammals.
In general, the present invention provides compounds of Formula I 
wherein
Aryl is phenyl, naphthyl, hetereoaromatic, substituted phenyl, substituted naphthyl, or substituted heteroaromatic;
X1 and X2 are both H or together form a bond between the C2 and the C3 carbon of the indole-ring of Formula I;
R1 is H, C1-C6 alkyl, substituted alkyl, aryl, or xe2x80x94C(O)O-t-butyl;
R2 is H, C1-C6 alkyl, substituted alkyl, aryl, or xe2x80x94C(O)O-t-butyl, provided that only one of R1 and R2 is xe2x80x94C(O)O-t-butyl;
R3 is H, halogen, C1-C6 alkyl, substituted alkyl, or aryl;
R4 is H, C1-C6 alkyl, substituted alkyl, or aryl;
Provided that R3 and R4 may not both be H;
R5 is hydrogen, halogen, C1-C4 alkyl, substituted alkyl, xe2x80x94Oxe2x80x94C1-C6 alkyl, substituted xe2x80x94Oxe2x80x94C1-C6 alkyl, CN, NO2, OH, xe2x80x94N3, NR1R2, xe2x80x94C(O)NR1R2, xe2x80x94C(S)NR1R2, xe2x80x94-O-aryl, or aryl;
and pharmaceutically acceptable salts thereof. They are useful for treating anxiety, depression, schizophrenia, stress-related disorders such as irritable bowel syndrome, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other central nervous system (CNS) disorders in humans and animals, including cognitive disorders such as mild cognitive impairment, Alzhiemer""s disease, and attention deficit disorder with or without hyperactivity.
The invention also provides a method for treating a disease or condition in a mammal, wherein the 5-HT6 receptor is implicated, comprising administering to a mammal a therapeutically effective amount of the compound of Formula 1. The invention further provides intermediates and processes to make the final compounds.
The invention still further provides isotopically-labeled compounds, which are identical to those recited in Formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature and means for using the isotopically labeled compounds in the performance of positron emission tomography and nuclear magnetic resonance imaging.
wherein
Aryl is phenyl, naphthyl, hetereoaromatic, substituted phenyl, substituted naphthyl, or substituted heteroaromatic;
X1 and X2 are both H or together form a bond between the C2 and the C3 carbon of the indole-ring of Formula I;
R1, is H, C1-C6 alkyl, substituted alkyl, aryl, or xe2x80x94C(O)O-t-butyl provided that only one of R1 and R2 is xe2x80x94C(O)O-t-butyl;
R2 is H, C1xe2x80x94C6 alkyl, substituted alkyl, aryl, or xe2x80x94C(O)O-t-butyl, provided that only one of R1 and R2 is xe2x80x94C(O)O-t-butyl;
Substituted alkyl is an alkyl moiety having from 1-6 carbon atoms, 0-3 substituents independently selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, and xe2x80x94I, and 0-1 substituent selected from xe2x80x94OR1xe2x88x920, xe2x80x94SR1xe2x88x920, xe2x80x94NR1xe2x88x920R1xe2x88x920, xe2x80x94C(O)R1xe2x88x920, xe2x80x94C(O)NR1xe2x88x920R1xe2x88x920, xe2x80x94CN, xe2x80x94NR1xe2x88x920C(O)R1xe2x88x920, xe2x80x94S(O)2NR1xe2x88x920R1xe2x88x920, xe2x80x94NR1xe2x88x920S(O)2R1xe2x88x920, xe2x80x94NO2, and aryl;
Each R1xe2x88x920 is independently selected from xe2x80x94H, C1-C6 alkyl, cycloalkyl, heterocycloalkyl, halogenated alkyl, halogenated cycloalkyl, halogenated heterocycloalkyl, or aryl;
Cycloalkyl is a cyclic ring moiety having from 3-6 carbon atoms;
Heterocycloalkyl is a cyclic ring moiety having from 4-7 atoms with 1-2 atoms within the ring selected from N, O, and S;
Halogenated alkyl is an alkyl moiety having from 1-6 carbon atoms and 1 to (2n+1) substituent(s) independently selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, and xe2x80x94I, where n is the maximum number of carbon atoms in the moiety;
Halogenated cycloalkyl is a cyclic ring moiety having from 3-6 carbon atoms and 1-4 substituents independently selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, and xe2x80x94I;
Halogenated heterocycloalkyl is a cyclic ring moiety having from 4-7 atoms with 1-2 atoms within the ring selected from N, O, and S, and 1-4 substituents independently selected from xe2x80x94F, xe2x80x94Cl, xe2x80x94Br, and xe2x80x94I;
R3 is H, halogen, C1-C6 alkyl, substituted alkyl, or aryl;
R4 is H, C1-C6 alkyl, substituted alkyl, or aryl;
Provided that R3 and R4 may not both be H;
R5 is hydrogen, halogen, C1-C4 alkyl, substituted alkyl, xe2x80x94OC1-C6 alkyl, substituted xe2x80x94OC1-C6 alkyl, CN, NO2, OH, xe2x80x94N3, NR1R2, xe2x80x94C(O)NR1R2, xe2x80x94C(S)NR1R2, xe2x80x94O-aryl, or aryl;
Substituted xe2x80x94OC1-C6 alkyl is an xe2x80x94OC1-C6 alkyl moiety in which the alkyl is a substituted alkyl;
Aryl is phenyl, naphthyl, hetereoaromatic, substituted phenyl, substituted naphthyl, or substituted heteroaromatic;
Heteroaromatic is a 5, 6, or 10 member heteroaromatic ring containing 1 to 3 hetero atoms selected from N, O, and S;
Substituted phenyl is a phenyl group having 1 to 3 substituents selected from halogen, C1-C4 alkyl, substituted C1-C6 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, substituted xe2x80x94Oxe2x80x94C1-C4 alkyl, CN, NO2, OH, xe2x80x94N3, NR1R2, xe2x80x94C(O)NR1R2, and xe2x80x94C(S) NR1R2;
Substituted naphthyl is a naphthyl group having 1 to 3 substituents selected from halogen, C1-C4 alkyl, substituted C1-C6 alkyl, xe2x80x94OC1-C6 alkyl, substituted xe2x80x94Oxe2x80x94C1-C4 alkyl, CN, NO2, OH, xe2x80x94N3, NR1R2, xe2x80x94C(O)NR1R2, and xe2x80x94C(S)NR1R2;
Substituted heteroaromatic is a heteroaromatic ring 1 to 3 substituents selected from halogen, C1-C4 alkyl, substituted C1-C6 alkyl, xe2x80x94OC1-C6 alkyl, substituted xe2x80x94Oxe2x80x94C1-C4 alkyl, CN, NO2, OH, xe2x80x94N3, NR1R2, xe2x80x94C(O)NR1R2, and xe2x80x94C(S)NR1R2, tetrazoyl, triazoyl, amidinyl, guanidinyl, thioguanidinyl, cyanoguanidinyl;
and pharmaceutically acceptable salts thereof are useful for treating anxiety, depression, schizophrenia, stress-related disorders such as irritable bowel syndrome, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other central nervous system (CNS) disorders in humans and animals, including cognitive disorders such as mild cognitive impairment, Alzhiemer""s disease, and attention deficit disorder with or without hyperactivity.
Embodiments of the invention may include one or more of the following. R1 is H, C1-C6 alkyl, or aryl. R2 is H, C1-C6 alkyl, or aryl. R3 is H, halogen, C1-C6 alkyl, or aryl. R4 is H, C1-C6 alkyl, or aryl. R5 is H. R3 is H or C1-C6 alkyl. R4 is H or C1-C6 alkyl. Aryl is phenyl or substituted phenyl. Substituted phenyl where the phenyl moiety is substituted with 1-3 substituents selected from H, halogen, C1-C4 alkyl, xe2x80x94Oxe2x80x94C1-C4 alkyl, and CF3. R1 and R2 are independently H or C1-C6 alkyl. Aryl is naphthyl or substituted naphthyl. Aryl is heteroaromatic or substituted heteroaromatic. X1 and X2 together form a bond between the C2 carbon and the C3 carbon of the indole-ring.
In another aspect, the invention features a compound or pharmaceutically acceptable salts thereof selected from the group consisting of:
2-[1-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine;
2-[2-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine;
N-methyl-2-[2-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine;
2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine;
2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N-methylethanamine;
2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N,N-dimethylethanamine;
2-{1-methyl-5-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}ethanamine;
N-methyl-2-{1-methyl-5-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}ethanamine;
2-{2-methyl-5-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}ethanamine;
2-{1,2-dimethyl-5-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}ethanamine;
2-{1,2-dimethyl-5-[(4-methylphenyl)sulfonyl]-1H-indol-3-yl}-N-methylethanamine;
2-(2-methyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-3-yl)ethanamine;
2-(1,2-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-3-yl)ethanamine;
2-(1,2-dimethyl-5-{[4-(trifluoromethyl)phenyl]sulfonyl}-1H-indol-3-yl)-N-methylethanamine;
2-{5-[(3-methoxyphenyl)sulfonyl]-2-methyl-1H-indol-3-yl}ethanamine;
2-{5-[(3-methoxyphenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine;
2-{5-[(3-methoxyphenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine;
2-{5-[(3,5-difluorophenyl)sulfonyl]-2-methyl-1H-indol-3-yl}ethanamine;
2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine;
2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine;
2-[2-methyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine, and
2-[1,2-dimethyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine.
In yet another aspect, the invention features a compound or pharmaceutically acceptable salts thereof, selected from the group consisting of: 2-[1-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine, 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine, 2-{5-[(3-methoxyphenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine, 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine, 2-[2-methyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine, 2-[1,2-dimethyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine, and 2-[1,2-dimethyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]-N-methylethanamine.
The compounds of formula I also can include isotopic labels. For example the compounds 2-[1-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine; 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N-methylethanamine; 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine; 2-[2-methyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine; and pharmaceutically acceptable salts thereof may contain an isotopic label such as at least one atom selected from Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18. Isotopically labeled compounds may be used in positron emission tomography.
In other embodiments, compounds 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine, and pharmaceutically acceptable salts thereof, each containing at least one 19F atom may be used in nuclear magnetic resonance imaging.
The compounds of the present invention are useful in the treatment of 5-HT6 implicated diseases or conditions, such as anxiety, depression, schizophrenia, stress-related disorders such as irritable bowel syndrome, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other central nervous system (CNS) disorders in humans and animals. Methods for treating a disease or condition in a mammal, in which 5-HT6 receptor is implicated, includes administering to a mammal, rectally, topically, orally, sublingually, or parenterally, from about 0.001 to about 100 mg/kg, e.g., from about 0.1 to about 50 mg/kg, of body weight of said mammal per day of compound(s) of Formula I.
The 5-arylsulfonyl indoles (I) of the present invention interact with serotonin receptors, such as 5-HT6 receptors, and are useful in the treatment of anxiety, depression, schizophrenia, Alzheimer""s disease, stress-related disorders such as irritable bowel syndrome, panic, a phobia, obsessive compulsive disorder, obesity, post-traumatic stress syndrome, epilepsy, and other CNS disorders. It is preferred that the 5-arylsulfonyl indole (I) be used to treat anxiety or depression.
To treat anxiety, depression, or other CNS diseases, the 5-arylsulfonyl indoles (I) are administered orally, sublingually, transdermally or parenterally to provide a dosage of about 0.1 to about 50 mg/kg/day. It is preferred that the dosage range be from about 0.1 to about 10 mg/kg/day. The 5-arylsulfonyl indoles (I) can be administered in divided doses either two, three or four times daily. For parenteral administration, a saline solution, dextrose solution, or water may be used as a suitable carrier. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art. It is preferred that the 5-arylsulfonyl indoles (I) be administered orally.
The exact dosage and frequency of administration depends on the particular 5-arylsulfonyl indole(s) used, the particular disease being treated, the severity of the disease being treated, the age, weight, general physical condition of the particular patient, other medication the individual may be taking as is well known to those skilled in the art and can be more accurately determined by measuring the blood level or concentration of the 5-arylsulfonyl indole (I) in the patient""s blood and/or the patient""s response to the particular condition being treated.
The 5-arylsulfonyl indole (I) compounds of the present invention may be incorporated into pharmaceutical compositions for treating different CNS diseases, such as anxiety or depression. The pharmaceutical compositions may include one or more 5-arylsulfonyl indole (I) compounds. The compositions also may contain well known carriers and excipients in addition to a therapeutically effective amount of compounds of Formula I. The term xe2x80x9ccarrierxe2x80x9d material or xe2x80x9cexcipientxe2x80x9d herein means any substance, not itself a therapeutic agent, used as a carrier and/or diluent and/or adjuvant, or vehicle for delivery of a therapeutic agent to a subject or added to a pharmaceutical composition to improve its handling or storage properties or to permit or facilitate formation of a dose unit of the composition into a discrete article such as a capsule or tablet suitable for oral administration. Excipients can include, by way of illustration and not limitation, diluents, disintegrants, binding agents, adhesives, wetting agents, polymers, lubricants, glidants, substances added to mask or counteract a disagreeable taste or odor, flavors, dyes, fragrances, and substances added to improve appearance of the composition. Acceptable excipients include lactose, sucrose, starch powder, cellulose esters of alkanoic acids, cellulose alkyl esters, talc, stearic acid, magnesium stearate, magnesium oxide, sodium and calcium salts of phosphoric and sulfuric acids, gelatin, acacia gum, sodium alginate, polyvinyl-pyrrolidone, and/or polyvinyl alcohol, and then tableted or encapsulated for convenient administration. Such capsules or tablets may contain a controlled-release formulation as may be provided in a dispersion of active compound in hydroxypropyl-methyl cellulose, or other methods known to those skilled in the art. For oral administration, the pharmaceutical composition may be in the form of, for example, a tablet, capsule, suspension or liquid. If desired, other active ingredients may be included in the composition.
In addition to the oral dosing, noted above, the compositions of the present invention may be administered by any suitable route, in the form of a pharmaceutical composition adapted to such a route, and in a dose effective for the treatment intended. The compositions may, for example, be administered parenterally, e.g., intravascularly, intraperitoneally, subcutaneously, or intramuscularly. For parenteral administration, saline solution, dextrose solution, or water may be used as a suitable carrier. Formulations for parenteral administration may be in the form of aqueous or non-aqueous isotonic sterile injection solutions or suspensions. These solutions and suspensions may be prepared from sterile powders or granules having one or more of the carriers or diluents mentioned for use in the formulations for oral administration. The compounds may be dissolved in water, polyethylene glycol, propylene glycol, ethanol, corn oil, cottonseed oil, peanut oil, sesame oil, benzyl alcohol, sodium chloride, and/or various buffers. Other adjuvants and modes of administration are well and widely known in the pharmaceutical art.
The invention also includes isotopically-labeled compounds, which are identical to those recited in Formula 1, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, iodine, and chlorine, such as 3H, 11C, 14C, 13N, 15O, 18F, 99mTc, 123I, and 125. Compounds of the present invention and pharmaceutically acceptable salts and prodrugs of said compounds that contain the aforementioned isotopes and/or other isotopes of other atoms are within the scope of the invention.
Isotopically-labeled compounds of the present invention are useful in drug and/or substrate tissue distribution and target occupancy assays. For example, isotopically labeled compounds are particularly useful in SPECT (single photon emission computed tomography) and in PET (positron emission tomography).
Single-photon emission computed tomography (SPECT), acquires information on the concentration of isotopically labeled compounds introduced to a mammal""s body. SPECT dates from the early 1960""s, when the idea of emission traverse section tomography was introduced by D. E. Kuhl and R. Q. Edwards prior to either PET, x-ray CT, or MRI. In general, SPECT requires isotopes that decay by electron capture and/or gamma emission. Example of viable SPECT isotopes include, but are not limited to, 123-iodine (123I) and 99m-technetium (99mTc). Subjects are injected with a radioactively labeled agent, typically at tracer doses. The nuclear decay resulting in the emission of a single gamma ray which passes through the tissue and is measured externally with a SPECT camera. The uptake of radioactivity reconstructed by computers as a tomogram shows tissue distribution in cross-sectional images.
Positron emission tomography (PET) is a technique for measuring the concentrations of positron-emitting isotopes within the tissues. Like SPECT, these measurements are, typically, made using PET cameras outside of the living subjects. PET can be broken down into several steps including, but not limited to, synthesizing a compound to include a positron-emitting isotope; administering the isotopically labeled compound to a mammal; and imaging the distribution of the positron activity as a function of time by emission tomography. PET is described, for example, by Alavi, et al. in Positron Emission Tomography, published by Alan R. Liss, Inc. in 1985.
Positron-emitting isotopes used in PET include, but are not limited to, Carbon-11, Nitrogen-13, Oxygen-15, and Fluorine-18. In general, positron-emitting isotopes should have short half-lives to help minimize the long-term radiation exposure that a patient receives from high dosages required during PET imaging.
In certain instances, PET imaging can be used to measure the binding kinetics of compounds of this invention with 5-HT6 serotonin receptors. For example, administering an isotopically labeled compound of the invention that penetrates into the body and binds to a 5-HT6 serotonin receptor creates a baseline PET signal which can be monitored while administering a second, different, non-isotopically labeled compound. The baseline PET signal will decrease as the non-isotopically labeled compound competes for the binding to the 5-HT6 serotonin receptor.
In general, compounds of formula I that are useful in performing PET or SPECT are those which penetrate the blood-brain barrier, exhibit high selectivity and modest affinity to 5-HT6 serotonin receptors, and are eventually metabolized. Compounds that are non-selective or those that exhibit excessive or small affinity for 5-HT6 serotonin receptors are, generally, not useful in studying brain receptor binding kinetics with respect to 5-HT6 serotonin receptors. Compounds that are not metabolized may harm the patient. Preferred compounds for isotopic labeling and use in performing PET or SPECT include 2-[1-methyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine; 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]-N-methylethanamine; 2-[1,2-dimethyl-5-(phenylsulfonyl)-1H-indol-3-yl]ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine; 2-[2-methyl-5-(1-naphthylsulfonyl)-1H-indol-3-yl]ethanamine; and pharmaceutically acceptable salts thereof.
In other embodiments, nuclear magnetic resonance spectroscopy (MRS) imaging can be used to detect the overall concentration of a compound or fragment thereof containing nuclei with a specific spin. In general, the isotopes useful in NMR imaging include, but are not limited to, hydrogen-1, carbon-13, phosphorus-31, and fluorine-19. For instance, compounds 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}ethanamine; 2-{5-[(3,5-difluorophenyl)sulfonyl]-1,2-dimethyl-1H-indol-3-yl}-N-methylethanamine; and pharmaceutically acceptable salts thereof, when containing 19F are useful in conducting NMR imaging.
Further, substitution with heavier isotopes such as deuterium, i.e., 2H, can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, maybe preferred in some circumstances. Isotopically labeled compounds of Formula I of this invention can generally be prepared by carrying out the synthetic procedures described above by substituting an isotopically labeled reagent for a non-isotopically labeled reagent.
The definitions and explanations below are for the terms as used throughout this entire document including both the specification and the claims.
The chemical formulas representing various compounds or molecular fragments in the specification and claims may contain variable substituents in addition to expressly defined structural features. These variable substituents are identified by a letter or a letter followed by a numerical subscript, for example, xe2x80x9cZ1xe2x80x9d or xe2x80x9cRixe2x80x9d where xe2x80x9cixe2x80x9d is an integer. These variable substituents are either monovalent or bivalent, that is, they represent a group attached to the formula by one or two chemical bonds. For example, a group Z1 would represent a bivalent variable if attached to the formula CH3xe2x80x94C(xe2x95x90Z1)H. Groups Ri and Rj would represent monovalent variable substituents if attached to the formula CH3xe2x80x94CH2xe2x80x94C(Ri) (Rj)xe2x80x94H. When chemical formulas are drawn in a linear fashion, such as those above, variable substituents contained in parentheses are bonded to the atom immediately to the left of the variable substituent enclosed in parenthesis. When two or more consecutive variable substituents are enclosed in parentheses, each of the consecutive variable substituents is bonded to the immediately preceding atom to the left, which is not enclosed in parentheses. Thus, in the formula above, both Ri and Rj are bonded to the preceing carbon atom. Also, for any molecule with an established system of carbon atom numbering, such as steroids, these carbon atoms are designated as Ci, where xe2x80x9cixe2x80x9d is the integer corresponding to the carbon atom number. For example, C6 represents the 6 position or carbon atom number in the steroid nucleus as traditionally designated by those skilled in the art of steroid chemistry. Likewise the term xe2x80x9cR6xe2x80x9d represents a variable substituent (either monovalent or bivalent) at the C6 position.
Chemical formulas or portions thereof drawn in a linear fashion represent atoms in a linear chain. The symbol xe2x80x9cxe2x88x92xe2x80x9d in general represents a bond between two atoms in the chain. Thus CH3xe2x80x94Oxe2x80x94CH2xe2x80x94CH(Ri)xe2x80x94CH3 represents a 2-substituted-1-methoxypropane compound. In a similar fashion, the symbol xe2x80x9cxe2x95x90xe2x80x9d represents a double bond, e.g., CH2xe2x95x90C (Ri)xe2x80x94Oxe2x80x94CH3.
The carbon atom content of variable substituents is indicated in one of two ways. The first method uses a prefix to the entire name of the variable such as xe2x80x9cC1-C4xe2x80x9d, where both xe2x80x9c1xe2x80x9d and xe2x80x9c4xe2x80x9d are integers representing the minimum and maximum number of carbon atoms in the variable. The prefix is separated from the variable by a space. For example, xe2x80x9cC1-C4 alkylxe2x80x9d represents alkyl of 1 through 4 carbon atoms, (including isomeric forms thereof unless an express indication to the contrary is given). Whenever this single prefix is given, the prefix indicates the entire carbon atom content of the variable being defined. Thus C2-C4 alkoxycarbonyl describes a group CH3xe2x80x94(CH2)nxe2x80x94Oxe2x80x94COxe2x80x94 where n is zero, one or two. By the second method the carbon atom content of only each portion of the definition is indicated separately by enclosing the xe2x80x9cCi-Cjxe2x80x9d designation in parentheses and placing it immediately (no intervening space) before the portion of the definition being defined. By this optional convention (C1-C3)alkoxycarbonyl has the same meaning as C2-C4 alkoxycarbonyl because the xe2x80x9cC1-C3xe2x80x9d refers only to the carbon atom content of the alkoxy group. Similarly while both C2-C6 alkoxyalkyl and (C1-C3)alkoxy(C1-C3)alkyl define alkoxyalkyl groups containing from 2 to 6 carbon atoms, the two definitions differ since the former definition allows either the alkoxy or alkyl portion alone to contain 4 or 5 carbon atoms while the latter definition limits either of these groups to 3 carbon atoms.
Alkyl is both straight- and branched-chain moieties having from 1-6 carbon atoms. For example, C1-6 alkyl includes methyl, ethyl, propyl, isopropyl, butyl, iso-butyl, sec-butyl, pentyl, 3-pentyl, hexyl, and isomeric forms thereof.
Ar refers to Aryl.
BOC refers to xe2x80x94C(O)O-t-butyl.
All temperatures are in degrees Centigrade.
HPLC refers to high pressure liquid chromatography.
DMSO refers to dimethylsulfoxide.
DMF refers to N,N-dimethylformamide.
Saline refers to an aqueous saturated sodium chloride solution.
Chromatography (column and flash chromatography) refers to purification/separation of compounds expressed as (support, eluent). It is understood that the appropriate fractions are pooled and concentrated to give the desired compound(s).
IR refers to infrared spectroscopy.
NMR refers to nuclear (proton) magnetic resonance spectroscopy, chemical shifts are reported in ppm (d) downfield from tetramethylsilane.
MS refers to mass spectrometry expressed as m/e, m/z or mass/charge unit. [M+H]+ refers to the positive ion of a parent plus a hydrogen atom. EI refers to electron impact. CI refers to chemical ionization. FAB refers to fast atom bombardment.
HRMS refers to high resolution mass spectrometry.
Pharmaceutically acceptable refers to those properties and/or substances which are acceptable to the patient from a pharmacological/toxicological point of view and to the manufacturing pharmaceutical chemist from a physical/chemical point of view regarding composition, formulation, stability, patient acceptance and bioavailability.
When solvent pairs are used, the ratios of solvents used are volume/volume (v/v).
When the solubility of a solid in a solvent is used the ratio of the solid to the solvent is weight/volume (wt/v).
Compounds of the present invention may be in the form of pharmaceutically acceptable salts. The term xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases, and salts prepared from inorganic acids, and organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, ferric, ferrous, lithium, magnesium, potassium, sodium, zinc, and the like. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, such as arginine, betaine, caffeine, choline, N,N-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, and the like. Salts derived from inorganic acids include salts of hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, phosphorous acid and the like. Salts derived from pharmaceutically acceptable organic non-toxic acids include salts of C1-6 alkyl carboxylic acids, di-carboxylic acids, and tri-carboxylic acids such as acetic acid, propionic acid, fumaric acid, succinic acid, tartaric acid, maleic acid, adipic acid, and citric acid, and aryl and alkyl sulfonic acids such as toluene sulfonic acids and the like.
By the term xe2x80x9ceffective amountxe2x80x9d of a compound as provided herein is meant a nontoxic but sufficient amount of the compound(s) to provide the desired effect. As pointed out below, the exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the disease that is being treated, the particular compound(s) used, the mode of administration, and the like. Thus, it is not possible to specify an exact xe2x80x9ceffective amount.xe2x80x9d However, an appropriate effective amount may be determined by one of ordinary skill in the art using only routine experimentation.
The 5-arylsulfonyl indoles of the present invention may be prepared using the following reaction schemes:
Arylsulphonylphenylhydrazines can be prepared by the reactions outlined in Chart 1. The appropriately substituted thiols (1) are either known to those skilled in the art or can be readily prepared from known starting materials by means well known to those skilled in the art. Thiol (1) is coupled with the appropriately substituted 4-chloro-1-nitrobenzene (2) by known means to produce the thioether (3). There can be either one or two R5 groups. If R5 is other than xe2x80x94H, it should be part of the 4-chloro-1-nitrobenzene (2) so that it will become part of the unsubstituted arylsulfone (8) when it is formed. It is most difficult to add the R5 substitutent (other than xe2x80x94H) to the unsubstituted arylsulfone (8) once it is formed. Therefore, the R5 group should be part of the appropriately substituted 4-chloro-1-nitrobenzene (2) when it is reacted with the thiol (1). R5 includes xe2x80x94H, xe2x80x94F and xe2x80x94Cl; it is preferred that R5 is xe2x80x94H. The thioether (3) is then oxidized with oxone followed by hydrogenation with rhodium on carbon (5%), all of which is known to those skilled in the art, to produce the amine (5). The amine (5) is then diazotized by (sodium) nitrite and (hydrochloric) acid followed by reduction with tin chloride to give the corresponding hydrazine (6). 
Compounds of formula I can be prepared by the reactions outlined in Chart 2. Grandberg reaction using hydrazine (6) with xcex3-chloroketones (7) gives the formation of the indole (8). The amino group is protected with Boc to give compound (9), in which the indole nitrogen is alkylated with cesium carbonate in acetone and alkylating reagents (e.g. Me2SO4, alkyl halides) . Compound (10) is further alkylated with sodium hydride and alkyl halides to generate compound (11). After deprotection, compound (12) is produced. Under reductive amination conditions with sodium cyanoborohydride in acetonitrile in the presence of aldehydes, compound (12) is converted to compound (13). The xcex3-chloroketones (7) are commercially available or can be made by procedures well known in the art. The procedures and conditions for the Grandberg, protection, deprotection, alkylation and reductive amination steps of Chart 2 are well known to those skilled in the art. 
Compounds of formula I can also be prepared by the reactions outlined in Chart 3. The Boc protected compound (9) is reduced with LiAlH4 to lead to the formation of the corresponding methyl compound (14). 
Compounds of formula I can also be prepared by the reactions outlined in Chart 4. The Boc protected compound (10) is treated with acids (e.g. HCl) to lead to the formation of the amino compound (15). 
Compounds of formula I can also be prepared by the reactions outlined in Chart 5. The indole compound (13) is treated with a reducing reagent such as sodium cyanoborohydride in an acid media such as trifluoroacetic acid or acetic acid to lead to the formation of the indoline compound (16). 